Parkinson's disease (PD) is a progressive neurodegenerative disease without a cure that affects one million people in North America. Simple and robust blood tests that can serve as surrogates of treatment response are critically needed to prioritize lead disease-modifying compounds in phase II and III clinical trials in PD. Rapidly advancing basic research is creating an expanding pipeline of candidate disease-modifying therapeutics that are entering clinical trials. Progress has been curtailed by a rate- limiting bottleneck. In small phase II clinical trials, testing safety & tolerability of a compound is straightforward, however they lack power to detect slowing of disease progression based on clinical assessments alone. Therefore every compound has to go through large, costly and time-consuming phase III clinical trials to make decisions about its neuroprotective efficacy or failure. Markers that track the progression of PD in phase II clinical trials and that can serve as surrogates of therapeutic effect are needed to prioritize lead compounds for phase III clinical trials. Recently, we performed an unbiased expression scan of 22,000 genes in 105 blood specimens from patients with PD and matched healthy and disease controls. In this cross-sectional study we identified and initially validated a 32-gene molecular marker associated with progression in PD. It included genes involved in cellular quality control directly relevant to the disease process. Here we will transform the microarray-based 32- gene progression signature into a clinically useful blood test based on quantitative PCR and rigorously validate it in a longitudinal study. We hypothesize that a simple test of disease progression can be derived from genome-wide expression changes in blood of patients with PD. Our Specific Aims are: 1 To transform the microarray-derived candidates into a simple, multigene test of progression in PD based on quantitative PCR; 2 To validate the multigene progression marker in a large longitudinal study of 150 cases and 150 controls assayed at baseline, one-, and two-year follow-up visits. This simple and non-invasive test for tracking disease progression will greatly accelerate the development of novel therapeutics for PD patients. PD affects one million individuals in North America and no medications are available to slow the disease process. Drug development has been curtailed by a rate-limiting bottleneck. In phase II clinical trials markers of disease progression that can serve as surrogates of therapeutic effect, are needed to prioritize lead compounds for phase III clinical trials. These progression markers will greatly accelerate the development of novel therapeutics for PD patients. [unreadable] [unreadable] [unreadable]